PROJECT 3: Malignant gliomas have a high mortality rate, short median length of survival and impart devastating consequences to both patients and family. The early identification of tumors responsive to therapy, versus those that are not, would greatly facilitate modifying an ineffective treatment regimen in a more timely fashion. During the initial funding period, we have translated preclinical studies on the utility of quantitative MRI techniques as early predictors of therapeutic efficacy in brain tumor patients. Our current clinical study is providing further evidence on the predictive value of diffusion MRI, particularly in terms of depiction of the spatial heterogeneity of response. In the proposed study we will intensify the scope of imaging to more ideally sample the evolution of multiple tissue properties over the treatment interval. Quantitative response indicators under investigation include serial measures of tumor water diffusion, blood volume and flow, and microvessel permeability. Pre-treatment proton metabolite status will also be assessed. Each indicator, in its own way, depicts biophysical properties which are relevant to tumor viability, cellular alteration by therapy, as well as accessibility of the tumor to therapy. In Specific Aim 1, we will perform detailed imaging measures on well defined patient populations enrolled in tree UMCC treatment protocols in order to obtain definitive validation of the clinical utility of quantitative MRI as an early predictor of treatment response measured a later date by standard criteria. In Specific Aim 2, we will investigate the ability of these measures to predict local therapeutic response by analyses of sub-tumor regions which exhibit clearly different patterns of local response apparent at a later date. Our overarching objective in pursuit of these aims is to demonstrate that biophysicaltissue properties measurable by noninvasive imaging are highly relevant to therapeutic outcome. Moreover, spatial heterogeneity of these properties are predictive of local failure, thus may form the basis for a rational design in spatially-directed treatment planning. Pub. Health: Overall, this research effort will provide the rationale for initiation of clinical trials with combinations of molecularly targeted therapies for the treatment of malignant brain tumors. In addition, imaging biomarkers for early assessment of treatment response will be identified and validated which will lead to individualization of patient treatment. University of Michigan Ann Arbor, Michigan PHS 398(Rev. 09/04) Page 213 Form Page 2 Principal Investigator/Program Director (Last, First, Middle): ROSS, Brian D. KEY PERSONNEL. See instructions. Use continuation pages as needed to provide the required information in the format shown below. Start with Principal Investigator. List all other key personnel in alphabetical order, last name first. Name eRA Commons User Name Organization Role on Project Chenevert, Thomas University of Michigan Project Leader Cao, Yue University ofMichigan Co-Investigator Gomez-Hassan, Diana University of Michigan Co-Investigator Heth, Jason University of Michigan Co-Investigator Junck, Larry Ljunck University of Michigan Co-Investigator Lawrence,Theodore University of Michigan Co-Investigator Maley Sundgren,Pia University of Michigan Co-Investigator McKeever, Paul University of Michigan Co-Investigator Pang, Yuxi University ofMichigan Co-Investigator Ten Haken, Randall University of Michigan Co-Investigator Tsien,Christina University of Michigan Co-Investigator OTHER SIGNIFICANT CONTRIBUTORS Name Organization Role on Project Human Embryonic Stem Cells [>$] No fl Yes If the proposed project involves human embryonic stem cells, list below the registration number of the specific cell line(s) from the following list: http://stemcells.nih.gov/reqistrv/index.asp. Usecontinuation pages as needed. If a specific line cannot be referenced at this time, include a statement that one from the Registry will be used. Cell Line Disclosure PermissionStatement. Applicable to SBIR/STTR Only. See SBIR/STTR instructions. [Yes No PHS 398 (Rev. 09/04) Page 214 Form Page 2-continued Number the following pages consecutively throughout the application. Do not use suffixes such as 4a, 4b. Principal Investigator/Program Director (Last, first, middle): Ross, Brian D. THROUGH DETAILED BUDGET FOR INITIAL BUDGET PERIOD FR[unreadable]M DIRECT COSTS ONLY Chenevert/Project 3 12/1/2006 11/30/2007 PERSONNEL (Applicant organization only) % DOLLAR AMOUNT REQUESTED (omit cents) TYPE EFFORT INST. ROLE ON APPT. ON PROJ. BASE SALARY FRINGE PROJECT NAME (months) SALARY REQUESTED BENEFITS TOTALS Project Leader Chenevert, Thomas 12 35% $160,680 $56,238 $16,871 $73,109 Co-Investigator Cao, Yue 12 5% $120,784 $6,039 $1,812 $7,851 Co-Investigator Gomez-Hassan, Diana 12 8% $183,500 $14,680 $4,404 $19,084 Co-Investigator Heth, Jason 12 5% $161,710 $8,086 $2,426 $10,512 Co-Investigator Junck, Larry 12 5% $169,529 $8,476 $2,543 $11,019 Co-Investigator Lawrence, Theodore 12 5% $183,500 $9,175 $2,753 $11,928 Co-Investigator Maly Sundgren, Pia 12 8% $183,500 $14,680 $4,404 $19,084 Co-Investigator McKeever, Paul 12 5% $150,447 $7,522 $2,257 $9,779 Co-Investigator Pang, Yuxi 12 5% $65,920 $3,296 $989 $4,285 Co-Investigator Ten Haken, Randall 12 5% $151,363 $7,568 $2,270 $9,838 Co-Investigator Tsien, Christina 12 15% $140,344 $21,052 $6,316 $27,368 Research TBN Associate 12 25% $44,290 $11,073 $3,322 $14,395 Research MRI Rohrer, Susan Tech 12 10% $58,931 $5,893 $1,768 $7,661 Clinical Brierley, Kristin Coordinator 12 20% $48,313 $9,663 $2,899 $12,562 SUBTOTALS "i $183,441 $55,034 $238,475 | CONSULTANT COSTS EQUIPMENT (Itemize) SUPPLIES (Itemize by category) Computer and Media Supplie $1 ,000 $1,000 TRAVEL Attendance to 1-2 Scientific Meetings per Year $1,200 PATIENT CARE COSTS INPATIENT OUTPATIENT 96 MRI's @ $700 Each $67,200 ALTERATIONS AND RENOVATIONS (Itemize by category) OTHER EXPENSES (Itemize by category) Publication Charges $1,000 Software Licensing $1,000 $2,000 CONSORTIUM/CONTRACTUAL COSTS DIRECT COSTS SUBTOTAL DIRECT COSTS FOR INITIAL BUDGET P (Item 7a, Face Page) $ 309,875 | CONSORTIUM/CONTRACTUAL COSTS FACILITIES AND ADMINISTRATION COSTS TOTAL DIRECT COSTS FOR INITIAL BUDGET PERIOD $ 309,875 I SBIR/STTR Only: FEE REQUESTED PHS 398 (Rev. 09/04) Page 215 Form Page 4